Reactive Oxygen Species in the Pathogenesis of Diabetic Complications

NCT ID: NCT00703989

Last Updated: 2019-11-12

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: NA
• Total Enrollment: 21 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2005-02-28
• Study Completion Date: 2008-02-29

Brief Summary

Benfotiamine blocks three major pathways of hyperglycemic damage and prevents experimental diabetic retinopathy and incipient nephropathy in these models. In cultured vascular cells, it also reduces aldose reductase gene expression, activity, and sorbitol levels. It does so by activating the enzyme transketolase. α-lipoic acid, a potent antioxidant, has also been reported to reduce both diabetic microvascular and macrovascular complications in animal models. To determine whether benfotiamine in combination with α-lipoic acid would normalize markers of ROS-induced pathways of complications in humans, we performed a pilot study in subjects with Type 1 diabetes using one daily dose of benfotiamine in combination with α-lipoic acid.

Detailed Description

The glycemic status of study patients was assessed by measuring baseline values of HbA1c, fructosamine, and fasting plasma glucose. Mean HbA1c was 8.7+ 0.7%, mean fructosamine was 421+29 mg/dl (normal range 174-286 mg/dl), and mean fasting blood glucose was 198+44 mg/dl.

At day 0, subjects levels of markers of two benfotiamine-sensitive pathways were determined: intracellular advanced glycation endproduct (AGE) formation, as reflected by a marker of increased intracellular methylglyoxal adducts in endothelial cells, angiopoietin 2 and hexosamine pathway activity, measured by determination of N-acetylglucosamine-modified protein in circulating monocytes. PKC activity in circulating monocytes could not be measured because the amount of blood required exceeded that approved by the Committee on Clinical Investigations. Serum levels of 6-keto-PGF-1 , a stable product produced by the nonenzymatic hydration of the antiatherogenic mediator prostacyclin were also determined. Subjects then took benfotiamine 300 mg twice a day, (Advanced Orthomolecular Research, Calgary, AB,CANADA) and slow-release α-lipoic acid (600 mg twice a day) (MRI, San Francisco, CA) for 28 days. Blood was obtained at day 0, day 15, and day 28.

Data were analyzed using 1-factor analysis of variance to compare the means of all the groups. The Tukey-Kramer multiple comparisons procedure was used to determine which pairs of means were different.

Conditions

Type 1 Diabetes

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

I

Patients with Type 1 diabetes

Group Type: EXPERIMENTAL

benfotiamine, α-lipoic acid

Intervention Type: DIETARY_SUPPLEMENT

benfotiamine 300 mg twice a day, (Advanced Orthomolecular Research, Calgary, AB,CANADA) and slow-release α-lipoic acid (600 mg twice a day) (MRI, San Francisco, CA) for a total duration of four weeks

II

Age-matched male subjects without Type 1 diabetes

Group Type: NO_INTERVENTION

No interventions assigned to this group

Interventions

benfotiamine, α-lipoic acid

benfotiamine 300 mg twice a day, (Advanced Orthomolecular Research, Calgary, AB,CANADA) and slow-release α-lipoic acid (600 mg twice a day) (MRI, San Francisco, CA) for a total duration of four weeks

Intervention Type: DIETARY_SUPPLEMENT

Other Intervention Names

benfotiamine 300 mg .slow-release; α-lipoic acid (600 mg twice a day)

Eligibility Criteria

Inclusion Criteria

• Male
• Type 1 diabetes duration between zero and fifteen years
• current insulin therapy

Exclusion Criteria

• Female
• proliferative retinopathy
• microalbuminuria
• symptomatic diabetic neuropathy
• cardiovascular disease
• taking medications
• smoking

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 45 Years
• Eligible Sex: MALE
• Accepts Healthy Volunteers: Yes

Sponsors

Juvenile Diabetes Research Foundation

OTHER

Sponsor Role: collaborator

National Institutes of Health (NIH)

NIH

Sponsor Role: collaborator

Albert Einstein College of Medicine

OTHER

Sponsor Role: lead

Responsible Party

Albert Einstein College of Medicien

Principal Investigators

Michael Brownlee, M.D.

Role: PRINCIPAL_INVESTIGATOR

Albert Einstein College of Medicine

Locations

GCRC, Albert Einstein College of Medicine

The Bronx, New York, United States

Countries

United States

References

Brownlee M. The pathobiology of diabetic complications: a unifying mechanism. Diabetes. 2005 Jun;54(6):1615-25. doi: 10.2337/diabetes.54.6.1615. No abstract available.

Reference Type: BACKGROUND

PMID: 15919781 (View on PubMed)

Du X, Edelstein D, Brownlee M. Oral benfotiamine plus alpha-lipoic acid normalises complication-causing pathways in type 1 diabetes. Diabetologia. 2008 Oct;51(10):1930-2. doi: 10.1007/s00125-008-1100-2. Epub 2008 Jul 29.

Reference Type: DERIVED

PMID: 18663426 (View on PubMed)

Other Identifiers

JDRF grant #8-2003-784

Identifier Type: -

Identifier Source: secondary_id

GCRC grant # MO1-RR12248

Identifier Type: -

Identifier Source: secondary_id

2004-582

Identifier Type: -

Identifier Source: org_study_id